New view of tumors’ evolution
Anne Trafton, MIT News Office
March 13, 2014
Cancer cells undergo extensive genetic alterations as they grow and
spread through the body. Some of these mutations, known as “drivers,”
help spur cells to grow out of control, while others (“passengers”) are
merely along for the ride.
MIT cancer biologists at the Koch Institute for Integrative Cancer
Research and geneticists from the Broad Institute have now performed the
most comprehensive analysis to date of these changes in mice programmed
to develop cancer. The team discovered mutations and other genetic
disturbances that arise at certain stages of lung cancer development;
the researchers were also able to identify tumor cells that broke free
to spread to other organs.
The findings, described in the March 13 issue of Cell,
suggest possible new targets for drugs for this aggressive form of
cancer, known as small cell lung cancer. There are now very few targeted
drugs for small cell lung cancer, a highly lethal form of lung cancer
that is associated with tobacco use and is usually treated with
chemotherapy drugs that have severe side effects.
“Right now, small cell lung cancer is really lagging behind with
respect to therapies that target a specific mutation or genetic
alteration in the tumors, because we don’t know a lot about the drivers
in these cancers,” says David McFadden, a postdoc at MIT’s Koch
Institute for Integrative Cancer Research and one of the lead authors of
the Cell paper.
Other lead authors of the paper are Koch Institute postdoc Thales
Papagiannakopoulos and Broad Institute researchers Amaro Taylor-Weiner,
Chip Stewart, and Scott Carter. Senior authors are Tyler Jacks, the
David H. Koch Professor of Biology and director of the Koch Institute,
and Gad Getz, director of cancer genome computational analysis at the
Broad Institute and director of the bioinformatics program at
Massachusetts General Hospital.
Tracking cancer progression
The research team studied a strain of mice that lacks two key
tumor-suppressor genes, p53 and Rb. These mice develop small cell lung
cancer, but scientists don’t know exactly how the cancer progresses or
which subsequent genetic alterations drive tumor growth.
In studies of human small cell lung cancer, it has been difficult to
identify these driver mutations because potent carcinogens in cigarette
smoke produce many mutations, most of which don’t affect tumor growth.
In the mouse model of the disease, fewer mutations arise because the
mice are not exposed to cigarette smoke, making it easier to identify
the key drivers.
Mice lacking p53 and Rb, the two most commonly mutated tumor
suppressors in human small cell lung cancer, develop lung tumors that
closely mimic the progression of human small cell lung cancer. These
tumors are highly metastatic and usually spread to the lymph nodes near
the lungs and then to the liver. The researchers isolated DNA from these
tumors and analyzed the genetic alterations that occurred, including
genetic mutations as well as changes in the number of copies of a gene
or chromosome.
First, the researchers compared genetic alterations that appeared
early and late in cancer development. They found that early on, tumors
accumulate many extra copies of a gene called Mycl1, a known oncogene
that helps cells ignore signals to stop growing. Because Mycl1 is
mutated so early, it is found in nearly all of the tumor cells, making
it a good drug target, McFadden says. There are currently no cancer
treatments that specifically target Mycl1, but scientists are now
working on drugs that target a closely related oncogene, MYC.
Later in tumor progression, the mouse cancer cells lose a gene called
Pten, which has previously been found mutated in about 20 percent of
small cell lung cancer patients. In normal cells, Pten regulates a
critical signaling pathway called PI3K, which influences many aspects of
cell growth and survival. When Pten is lost, the pathway becomes
overactive, allowing tumor cells to grow very rapidly.
Drugs that target the PI3K pathway are now in the early stages of clinical testing in human patients.
Retracing metastasis
The researchers also compared the genomes of cells from the original
lung tumors and from tumors that later appeared in other sites. This
enabled them to retrace the tumor cells’ paths and to determine which
lung tumors were the sources of the metastases. They found that while
multiple subsets of cells from the lung tumors could move to the lymph
nodes, usually only a single subset from the lymph nodes spread to the
liver.
“Our data really add to this emerging idea that metastatic spread is
quite complicated, and that there may be different populations within a
single cancer moving around to different sites, which may complicate
treatments,” McFadden says.
The approach taken by the MIT and Broad team offers a unique
opportunity to study the mechanisms that underlie lung cancer
development and spread, says Anton Berns, a research group leader at the
Netherlands Cancer Institute.
“This is of interest, as it can reveal that there might or might not
be a specific route, and that there is a specific order in which
selections for mutations do take place. In this regard this is a
landmark paper,” says Berns, who was not part of the research team. “It
is a beautiful, detailed dissection of tumor development in the mouse,
carefully executed with great attention for what such a system can
teach.”
The researchers now hope to perform further genetic analysis to
identify which mutations make certain cells more likely to metastasize.
They also plan to try treating small cell lung tumors with chemotherapy
drugs and observing the genetic changes that occur as cancer cells
become resistant to treatment.
The study was funded by the Ludwig Center for Molecular Oncology at
MIT, the Howard Hughes Medical Institute, the National Human Genome
Research Institute, a National Institutes of Health-National Cancer
Institute Career Development Award, and a Hope Funds for Cancer Research
Fellowship.
Reposted from: http://news.mit.edu/2014/new-view-of-tumors-evolut…
